Single Pass Transmembrane Receptor Signaling

Question 1

Which single pass receptors have their kinase as part of their intracellular domain?

Answer 1

Intrinsic kinase, RTKs, and TGFB receptors

Question 2

Which single pass membrane receptors have the kinase as a separate protein?

Answer 2

Extrinsic kinase, cytokine receptors

Question 3

JAK/STAT is an example of what kind of receptor?

Answer 3

Cytokine receptor

Question 4

JAK/STAT pathway

Answer 4

1. Cytokine receptor binds ligand
2. Receptor dimerizes, bringing together the JAK kinases in the intracellular domain
3. The JAKs autotransphosphorylate on tyrosines of their Lip domain
4. Activated JAK phosphorylates tyrosines on the receptor’s intracellular domain
5. Phosphotyrosines recruit STAT via its SH2 docking site
6. JAK phosphorylates STAT
7. STAT dimerizes through its own SH2 domains and phosphotyrosine residues, then goes to the nucleus to mediate transcriptional gene expression

Question 5

Where is erythropoitetin produced? Where does it work?

Answer 5

Produced in the kidneys; stimulates RBC prodouction in bone marrow

Question 6

In cytokine receptors, the phosphotyrosine residues on the intracellular domain of the receptor serve to

Answer 6

dock a scaffold of proteins that have SH2, SH3, or PTB domains; these proteins allow for further phosphorylation or recruits additional signaling proteins in the cascade

Question 7

JAK

Answer 7

Extrinsic protein kinase that is associated with the intracellular domain of a cytokine receptor, but is a separate protein

Question 8

Which signaling pathway is involved in responding to interferons? What are interferons?

Answer 8

JAK/STAT

Interferons bind to cells to stimulate an antiviral response.

Question 9

Which signaling pathway is associated with lactation?

Answer 9

JAK/STAT generates prolactin signals to alter the metabolism of mammary cells for milk produciton

Question 10

Erythropoietin (Epo) - what does it do and and what kind of receptor does it use?

Answer 10

Stimulates RBC production.

Epo receptor is a cytokine receptor that mediates proliferation & differentiation of the erythroid progenitor cell into mature RBCs.

Question 11

Multiple sclerosis

Answer 11

Autoimmune disease in which T cells and monocytes degrade the myelin sheath

• remission & recurrence
• fatigue, trouble walking & balance, muscle weakness, blurred vision
• can result from viral infections (Epstein-Barr, Herpes virus-6)

Question 12

Treatment fo rMS

Answer 12

Steroids reduce inflammation

Interferons signal the cytokine JAK/STAT pathway to produce anti-inflammatory signals while inhibiting pro-inflammatory signals

Question 13

Monomeric G proteins play an integral role in what kind of receptors?

Answer 13

RTKs

Question 14

GEF vs GAP

Answer 14

GEF turns on the monomeric G-protein by exchanging the GDP for GTP

Question 15

While RTKs have intrinsic tyrosine kinase domains and cytokine receptors have extrinsic ones, how are the receptors similar?

Answer 15

Both exist as a monomer, whose ligation promotes dimerization > brings together the kinase domains for autophosphorylation of the Lip domain and activation of the kinase > kinase phosphorylates intracellular Tyrs > phosphotyrosines serve as dockign sites for protein-protein interacitons with other intracellular signaling molecules > signal amplification > altered gene expression and cellular fxn

Question 16

The Ras-MAP kinase pathway uses what kind of receptor?

Answer 16

RTK

Question 17

Describe the Ras-MAP kinase pathway, starting from the receptor phosphotyrosines

Answer 17

1. Receptor phosphotyrosines dock GRB2 and SOS thorugh SH2 & SH3
2. SOS is a GEF for Ras, so it activates it
3. Activated Ras-GTP can now activate the MAPK pathway (Ras-Raf-Mek-Erk)
4. Erk/MAP kinase dimerizes and goes to the nucleus to phosphorylate and activate tf’s

Question 18

How can Ras mutations cause cancer?

Answer 18

If Ras can’t hydrolyze GTP (such as in RAS^Gly12), it’s permanently active and will stimulate continual MAPK activity –> cancer growth

Question 19

What type of receptor includes many growth factor receptors such as EGFR, PDGFR,FGFR, VEGFR, RET

Answer 19

RTKS

Question 20

The insulin receptor is what type of receptor?

Answer 20

RTKs involved in metbaolism

Question 21

type 2 diabetes can result form a defect in what type of receptor?

Answer 21

RTK - the insulin receptor is an RTK involved in glucose and lipid metabolism pathways

Question 22

Why are HER2 monoclonal antibodies effective in treating HER2 positive breast cancers?

Answer 22

HER2 is an RTK that promotes growth.

Question 23

What is TGFB? What does it result in?

Answer 23

The ligand of the Smad signaling pathway, which leads to secretion of ECM proteins from epithelial and fibroblast cells

Question 25

TGFB/Smad Signalign pathway

Answer 25

1. TGFB (ligand) binds its already-phosphorylated RII receptor
2. RII receptor phosphorylates & activates RI on its intracellular domain
3. RI phosphorylates SMAD transcription factors
4. Smad3 unmasks a nuclear localization sequence
5. Two Smad3’s and a Smad4 combine into a trimer through phosphorylation interactions and enter the nucleus via importin to cause changes in gene expression

Question 26

What does TGFB signaling do?

Answer 26

• Secretion of ECM proteins from epithelial and fibroblast cells
• Secretion of serum protease inhibitors (which degrade ECM proteins)
• Signals for Cycling-Dependent Kinase Inhibitor (CDKI) p15, which causes cell cycle arrest

Question 27

What signaling pathway is anti-growth? How?

Answer 27

TGFB/Smad

• Secretion of PAI1 suppresses migraiton into tissues by forming a new tissue
• CDKI p15 causes cell cycle arrest

Question 28

Smad4 is assocaited with what type of cancer?

Answer 28

Pancreatic cancer ; originally, Smad4 was called Deletion in Pancreatic Cancer (DPC

Question 29

Reitnoblastoma, colon, and gastric cancers have what problem with the TGFB pathway?

Answer 29

RI or RII receptosr are deleted